Primary alcohols from thiocarboxylic acids and esters



Patented May 23, 1950 PRIMARY ALcouoLs mom moccanoxruc acms AND ns'raasLeopold Buaicka and Vladimir Prclog, Zurich,

Switaerland,

aslignentoGibaIimltedBaale,

Switzerland, a Swiss ii:-

No Drawing. App

herein to denote acids containing the group on V p and as thiocarboxylicacid esters are meant compounds containing the residue In the process ofthe invention a reductive desulphurization takes place with theformation of a primary alcohol. The process is quite generallyapplicable to aliphatic, alicyclic, aromatic or heterocyclicthiocarboxylic acids containing more than two carbon atoms and estersthereof. 'The starting materials may also contain substituents,

for example, hydrocarbon radicals or substituted or unsubstitutedhydroxyl, carboxyl or amino groups. The thiocarboxylic acid group orester group may be bound to a primary, secondary or tertiary carbonatom. As compared with the free thiocarboxylic acids, the esters, suchas the methyl or benzyl esters, have the advantage that they are morestable. The aforesaid starting materials can be obtained easily and ingood yield, by the action of the corresponding acid chloride onpotassium hydrosulilde or on a mercaptan in the presence of a tertiaryamine such as pyridine, triamylamine and the like.

As finely divided metals ch ged with hydrogen there are used, forexample, catalysts such as are obtained by the decomposition of thesocalled Raney alloys with solutions of caustic alkalies. Especiallysuitable is Raney nickel. Alternatively, there may be used othersuitable pretreated metals charged with hydrogen, for example, Raneyiron or Raney copper.

The reaction conditions may vary within widelimits. Thus, the reactionmay be conducted with Raney nickel in the presence or absence ofsolvents such, for example, as ether, aliphatic alcohols or dioxane, asolvent being advantageously "cation i1'l9l4lNo. 724,91}. ll SwitaerlandFebruary 6,

January 28, 1947, Se-

2 used which contains no water or only small quantities thereof. Thereaction generally occurs at room temperature with the evolution ofheat. In certain cases however, it is of advantage to heat the reactionmixture in order to accelerate the reaction.

The invention also includes the manufacture of a primary alcohol bystarting from a carboxylic acid with the intermediate production of thecorresponding thiocompounda In this manner, for example, palmitic acidcan be converted into cetyl alcohol, benzoic acid into benzyl alcohol,pentaaeetyl-gluconic acid into pentaacetylsorbitol,lid-acetoxy-etio-allocholanic acid into 33-acetoxy-etio-allocholanyl-methanol, and acetyloleanolic acid intomonoacetylerythrodiol. A special advantage of this process is that itcan be carried out in a neutral medium under mild conditions, so thatsensitive or easily reducible res- 2 idues present in the moleculeremain unchanged.

Thus, for example, pyridine carboxylic acids can be reduced to thecorresponding hydroxymethylpyridines. It is also possible to obtainaminoalcohols from amino-carboxylic acids. When acylamino-carboxylicacids are used there are obtained amino-alcohols in which theamino-group is free or acylated depending on the nature of the acylresidue. Thus, for example, a carbobenzoxy-group is split of! during thereduction, whereas this does not occur in the case of a benzoyl group.It has also been found that optically active amino-alcohols can beobtained by the proces of the invention from optically activeaminocarboxylic acids.

On the other hand, the hitherto known general processes for convertingcarboxylic acids into primary alcohols, for example, the reduction ofthe esters with sodium and absolute alcohol or the catalytichydrogenation of the esters under raised pressure and at hightemperature, have the disadvantage that they are not applicable in thecase of carboxylic acids which are sensitive to alkalies or are notstable at high temperatures. Thus, for example, the reduction ofpyridine carbonlic acids by these known processes leads to piperidinederivatives. Furthermore, the reduction of amino-carboxylic acids toamino-alcohols does not in general proceed smoothly. In particular ithas not been possible hitherto to bring about the reduction of opticallyactive aminocarboXYlic acids to amino-alcohols without extensiveracemisation.

It is also possible by means of the present proces in the case ofpolyearboxylic acids to convert only certain of the carboxyl groups intothe cor-,

responding residues containing sulphur, and in this manner to producehydroxy-carboxylic acids from polycarboxylic acids.

The action of Raney nickel on compounds containing sulphur has beeninvestigated by J. Bougault, E. Cattelain and P. Chabrier [ComptesRendus dc lAcademie des Sciences, vol. 208, page 657 (1939); Bulletin dela Socit Chimique de France vol. 6, page 34 (1939) and vol. 7, page 781(1940)]; and also by R. Monzingo, D. E. Wolf, S. A. Harris and K.Folkers [Journal of the American Chemical Society, vol. 65, page 10131943)] Furthermore, the reductive desulphurization by means of Raneynickel has been described by the following authors: V. du Vigneaud andco-workers [Journal of Biological Chemistry, vol. 146, page 475 (1942)l; T. Reichstein and coworkers (Experientia, vol. 1, page 386 (19.45)]:N. K. Richtmeyer, C. J. Carr and C. 8. Hudson [Journal of the AmericanChemical Society, vol. 65, page 1477 (1943)]; E. Schwenk and co-workersJournal of Organic Chemistry, vol. 9, page 1 (1944)]; H. Hauptmann[British Chemical Abstracts, 1945, vol. II. D8' e'245]; and M. L.Wolfrom and J. V. Karabinos [Journal of American Chemical Society, vol.65, page 909 (1944)].

Among these authors only Bougault and coworkers (100. cit.) treated athiocarboxylic acid, namely, thioacetic acid with Raney nickel. Theyobserved the formation of acetic acid in aqueous medium and acetaldehydein absolute alcoholic medium.

From the foregoing literature references it could not be foreseen thatthat the reductive desulphurization in the case of thiocarboxylic acidsand esters thereof would lead to the production of primary alcohols. Itis surprising that pri- 7 mary alcohols could be obtained in thismanner.

The products of the invention can be used for various purposes dependingon their properties or serve as intermediate products.

The invention is described in greater detail in the following exampleswhich are presented by way of illustration and not of limitation. In theexamples, the quantities given are parts by weight.

Example 1 mixture is freed from the catalyst by filtration,

thoroughly washed, and evaporated to dryness. The residue is dissolvedin petroleum etherbenzene (1:1), and adsorbed over aluminium oxide, andelutriated with benzene-ether and ether methanol (1:1), whereby purecetyl alcohol is obtained which melts at 46-47.5 C. afterrecrystallisation from acetone.

Example 2 2 parts of thiobenzoic acid (Beilstein, 4th ed.. vol. 9.System No. 419) are added to a suspension of 18 parts of Raney nickel in100 parts of aqueous ethanol of about 95 per cent. strength. The mixtureis stirred for a few hours. It is then filteredand the resulting benzylalcohol melting at 204 C. is recovered from the filtrate. Itsphenylurethane melts at -76 C.

Example 3 5 parts of Raney nickel are added in portions to 1 part ofthiopalmitic acid S-methyl ester [A. W. Ralston, E. W. Segebracht and S.T. Bauer, Journalof Organic Chemistry, vol. 4, page 502 (1939)] in 100parts of boiling aqueous ethanol of about per cent. strength. Afterworking up.-

1 part of thiobenzoic acid S-methyl ester lObermeyer, Berichte derdeutschen chemischen Gesellschaft, vol. 20. page 2922 (1887)] is heatedto boiling in parts of ethanol. 5 parts of Raney nickel are then added,and the whole is heated for a short time longer in a, reflux apparatus,filtered to remove the catalyst. and the benzyl alcohol is isolated fromthe filtrate.

Benzyl alcohol is also obtained by carrying out the reaction in aqueousethanol of about 70 per cent. strength.

Example 5 A solution of 1 part of thionicotinic acid 8- methyl ester (B.P.1-x 124 0.: obtained from nicotinic acid chloride and methylmercaptan) in parts of ethanol is boiled in a reflux apparatus for ashort time with 5 parts of Raney nickel. The whole is then filtered,thoroughly washed several times with aqueous ethanol, andfl-hydroxymethyl-pyridine is isolated from the filtrate by forming thepicrate, which melts at 162-163 C.

Example 6 3p-acetoxy-etio-allothiocholanic acid S-methyl ester (meltingat 158l59 0.; obtained from 33- acetoxy-etio-allocholanic acid chlorideand methyl mercaptan in presence of pyridine) is treated with Raneynickel in a. manner analogous to that described in the foregoingexamples. The

resulting product is dissolved in benzene and chromatographed overaluminium oxide. There is obtained3fl-acetoxy-etio-allocholanyl-methanol, which melts at 141-142" C.. in ayield of 93 per cent.

By starting from A -3fl-acetoxy-etio-thiocholenic acid S-methyl estermelting at 183-184" C. there is obtained in a similar manner A-3pm.cetoxy-etio-cholenyl- 17) -methanol, which forms needles melting at157-158 C.

Example 7 Pentacetyl-sorbitol is obtained in an analogous a0 manner frompentacetyl-thiogluconic acid S- methyl ester (melting at 92-93 (3.;obtained from pentacetyl-gluconic acid chloride and methyl mercaptan inpresence of pyridine). By subsequent acetylation with acetic anhydrldethere is obtained hexacetyl-sorbitol melting at 100 C.

Example 8 5 parts of acetyl-thioleanolic acid S-metbyl ester (melting at167-168 C.; obtained from acetyl-oleanolic acid chloride and methylmercaptan in presence of triamylamine) are treated with 60 parts ofRaney nickel m 200 parts of ethanol to yield erythrodiol monoacetatemelting at 2385-2239" C. By subsequent acetylation there is obtainedfrom the latter product the known erythrodiol diacetate lzimmermann,Helvetica Chimica Acta, vol. 19, page 247 (1936) l.

Example 9 By treating tetradecane-l l-carboxylic acid 5 methylester-l-thiocarboxylic acid S-methyl ester (melting at 52-53 0.;obtained fromthapsic acid methyl ester acid chloride and methylmercaptan in pyridine) in ethereal solution in an analogous manner,there is obtained by reductive desulphurisation15-hydroxy-pentadecane-1-carboxylic acid methyl ester melting at 54-55C.

Example 10 24 parts of benzoylamino-thioacetic acid S- methyl ester(melting at 1l9.5-12l.5 C. obtained from benzoylaminoacetyl chloride andmethyl mercaptan in pyridine) are treated in 400 parts of ethanol with250 parts of Raney nickel for a Example 11 In a manner analogous to thatdescribed in the preceding example an ethereal solution of N-carbobenzoxy-d-thioalanine S-methyl ester (melting at 49-50 C.; obtainedby the reaction of the chloride obtained from carbobenzoxy-d-(-)-alaninewith methyl mercaptan in pyridine) is treated with Raney nickel. Afterthe reductive desulphurisation the product is freed from the catalyst byfiltration, and washed with alcohol. The filtrate is then acidified withhydrochloric acid, and'the acid solution is evaporated to dryness. Inthis manner d-(-)-alaninol hydrochloride is obtained. By allowing thehydrochloride to stand overnight with para-bromobenzoyl chlo- I ride inpyridine the .0:N-di-para-bromobenzoyl derivative is formed. The latteris purified in benzene solution by chromatography over aluminium oxide,and recrystallisation from ben- Zeno-petroleum ether. The product meltsat 155 C.

Having thus described the invention claimed is:

1. The process of preparing primary alcohols which comprises treating amember selected from what is the group consisting of thiocarboxylicacids hav- 6o ing more than 2 carbon atoms and esters thereof with Raneynickel.

2. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of thiocarboxylic acids havingmore than 2 carbon atoms and esters thereof with Raney nickel in aneutral organic solvent, and recovering the primary alcohol thusproduced.

8. The proceot primary alcohols which-comprises treating a memberselected from the group consisting of aminothiocarboxylic acids havingmore than 2 carbon atoms and esters thereof with Raney nickel.

4. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of acylaminothiocarboxylicacids having more than 2 carbon atoms and esters thereof with Raneynickel.

5. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of optically activeacylaminothiocarboxylic acids having more than 2 carbon atoms and estersthereof with Raney nickel.

6. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of aminothiocarboxylic acidshaving more than 2 carbon atoms and esters thereof with Raney nickel ina neutral solvent, and recovering the primary alcohol thus produced.

'7. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of acylaminothiocarboxylicacids having more than 2 carbon atoms and esters thereof with Raneynickel in a neutral organic solvent, and recovering the primary alcoholthus produced.

8. The process of preparing primary alcohols which comprises treating amember selected from the group consistin of optically activeacylaminothiocarboxylic acids having more than 2 carbon atoms and estersthereof with Raney nickel in a neutral organic solvent, and recoveringthe primary alcohol thus produced.

9. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of pyridinethiocarboxylicacids and esters thereof 'with Raney nickel.

10. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of pyridinethiocarboxylicacids and esters thereof with Raney nickel in a neutral organic solvent,and recovering the primary alcohol thus produced.

11. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of free and esterifiedthiocarboxylic acids containing an esterified carboxyl group with Raneynickel.

12. The process of preparing primary alcohols which comprises treating amember selected from the group consisting of free and esterifiedthiocarboxylic acids containing an esterified carboxyl group with Raneynickel in a neutral organic solvent, and recovering the primary alcoholthus produced.

LEOPOLD RUZICKA. VLADIMIR PRELOG.

REFERENCES CITED The following references are of record in the file ofthis patent:

Bougault et al., Comptes Rendus 208, 657

1. THE PROCESS OF PREPARING PRIMARY ALCOHOLS WHICH COMPRISES TREATING AMEMBER SELECTED FROM THE GROUP CONSISTING OF THIOCARBOXYLIC ACIDS HAVINGMORE THAN 2 CARBON ATOMS AND ESTERS THEREOF WITH RANEY NICKEL.